ITULAZAX® versus Alutard SQ® in the treatment of allergic rhinitis induced by pollen from the birch homologous group: A cost‐minimization modeling analysis from the Danish societal perspective

Abstract Background and aims Allergic rhinitis (AR) is an inflammatory disorder triggered by an allergic immune response to inhaled allergens. Birch pollen is the major allergenic tree pollen in parts of Europe. ITULAZAX® is a sublingual immunotherapy tablet for the treatment of adults with moderate‐to‐severe AR and/or conjunctivitis induced by pollen from the birch homologous group. The aim was to compare the costs of treating AR with ITULAZAX® versus subcutaneous ALUTARD SQ® Betula verrucosa (ALUTARD SQ®) from a Danish societal perspective. Methods A cost‐minimization model was developed to capture costs of allergy immunotherapy (AIT), interactions with healthcare professionals (HCPs) in three different care settings (general practice, allergy specialist, and hospital), and indirect costs arising from absenteeism and presenteeism. The cost‐minimization analysis was conducted over a 3‐year time horizon with costs reported in 2021 Danish Kroner (DKK) and Euros (EUR) based on the European Central Bank 365‐day average exchange rate. One‐way sensitivity analyses were performed. Results The base case analysis showed that the total cost of treatment over 3 years was estimated to be DKK 49,117 (EUR 6598) per patient with ALUTARD SQ®, compared with DKK 30,996 (EUR 4164) with ITULAZAX®, reflecting a cost saving of DKK 18,121 (EUR 2434) per patient with ITULAZAX® over 3 years. Over the 3‐year time horizon, costs of AIT were predicted to increase by DKK 17,928 (EUR 2408) with ITULAZAX®, while costs of interactions with HCPs were predicted to decrease by DKK 22,528 (EUR 3027) versus ALUTARD SQ®, more than offsetting the increased cost of ITULAZAX®. Conclusions Given the equivalent effectiveness of the two AIT products, and the cost savings with ITULAZAX® versus ALUTARD SQ® from a Danish societal perspective, ITULAZAX® should be considered as a cost‐saving alternative to ALUTARD SQ® for the treatment of birch pollen‐induced moderate‐to‐severe AR in adults.

Furthermore, AR shares elements of pathology and pathophysiology with allergic asthma, which frequently co-exists with AR in the same individual 2,3 ; up to 30% of patients with AR have concomitant asthma, and more than 70% of patients with asthma have concomitant AR. 4,5 AR and allergic asthma share a common systemic immunoglobulin E (IgE)-mediated immunological response to inhaled allergens, 2, 6 and AR has been identified as a key risk factor for developing asthma. [7][8][9] The most common inhalant allergens causing AR include pollen, dust mites, dander, and insects. 1,10 Birch pollen is the major allergenic tree pollen in parts of Europe, and is also listed among the key pollen allergens in North America. 10,11 Birch pollen contains the major allergen Bet v 1, which is homologous with allergens from other trees in the Fagales order. The birch homologous group is defined by the European Medicines Agency as including alder, beech, hazel, hop/hornbeam, oak, and chestnut. 12,13 The cross-reactive nature of allergens and the sequential flowering of trees in the birch homologous group can result in individuals with birch pollen-induced AR experiencing symptoms for a prolonged period, extending beyond the birch pollen season. 14 Cross-reactivity may also expand the geographical area in which an allergic reaction may be triggered.
The diverse range of moderate-severe symptoms combined with the long duration of birch and cross-reactive allergen exposure can combine to make birch pollen-induced AR a significant, debilitating disease that can affect many aspects of a person's life. Based on current guidelines, patients are encouraged to attempt to reduce symptoms of AR through allergen avoidance or, where allergen avoidance is neither possible nor effective, to take one of two forms of AR treatment recommended by clinical guidelines: allergy pharmacotherapy, or allergy immunotherapy (AIT). The Allergic Rhinitis and its Impact on Asthma guidelines recommend the use of secondgeneration non-sedating oral or intranasal H 1 -antihistamines to treat the symptoms of AR, in combination with an intranasal corticosteroid or leukotriene receptor antagonist in cases where the symptoms are moderate/severe. 15 AIT is then recommended in patients with moderate/severe AR and/or conjunctivitis who have a clinical history of symptoms despite use of symptom-relieving medication and have a diagnosis of IgE-mediated allergy. 15 ITULAZAX® (SQ tree SLIT-tablet) is a new sublingual immunotherapy (SLIT) tablet for the treatment of moderate-to-severe AR and/or conjunctivitis induced by pollen from the birch homologous group, indicated in adult patients with a clinical history of symptoms despite use of allergy pharmacotherapy and a positive test of sensitization to a member of the birch homologous group (skin prick test and/or specific IgE). The safety and efficacy of ITULAZAX® was demonstrated in the TT-04 trial, a large-scale, prospective Phase III, randomized, parallel-group, double-blind, placebo-controlled multicenter study. 16,17 TT-04 showed that ITULAZAX® resulted in a significant reduction in AR symptoms and medication use relative to placebo, with the total combined rhinoconjunctivitis symptom and medication score reducing by 39.6% during the birch pollen season (p < 0.0001). 16,17 Relative to subcutaneous immunotherapy (SCIT) products such as ALUTARD SQ® Betula verrucosa (ALUTARD SQ®), the sublingual administration of SLIT-tablets offers several advantages, including at-home administration, and increased convenience, especially for those living far from treatment facilities. 18 A systematic review of cost data on AR in selected European countries (Denmark, France, Germany, Italy, and Sweden) concluded that there is a considerable economic burden associated with AR, driven mainly by indirect costs arising from high levels of absenteeism and presenteeism. 19 Given this economic burden and the increasing pressure to optimize healthcare expenditure, the objective of the present study was to evaluate the relative costs of ITULA-ZAX® and ALUTARD SQ® Betula verrucosa in the treatment of moderate-to-severe AR from a societal perspective in Denmark.

| Cost-minimization analysis and model
Cost-minimization was selected as the most appropriate analysis methodology (as opposed to a cost-effectiveness, cost-benefit, or cost-utility analysis) based on the assumption that ITULAZAX® and ALUTARD SQ® are clinically equivalent. While no head-to-head randomized trial data are available comparing ITULAZAX® with ALUTARD SQ®, a placebo-controlled, randomized controlled trial (RCT) comparing the efficacy of SLIT and SCIT in the treatment of adults with birch pollen allergy showed no significant differences in rhinoconjunctivitis symptom scores or medication scores between SLIT and SCIT. 20 The assumption of equivalence was further supported by analyses comparing SLIT and SCIT products in patients sensitized to other allergens. For instance, two meta-analyses comparing SLIT-tablets with SCIT in individuals with grass pollen allergy concluded that their efficacy was comparable. 21,22 Furthermore, a 2017 review by Brunton et al. reported that five small (N ≤ 71 patients) head-to-head, double-blind, placebo-controlled trials had directly compared the efficacy of SLIT with SCIT, including the aforementioned birch pollen allergy RCT, noting that "in the four trials that conducted statistical analyses, no significant differences in symptom scores were found between SCIT and SLIT". 23 It has also been demonstrated that, regardless of the administration route, AIT results in similar immunologic changes including increased IgG4-levels. 24 Previous economic comparisons of SCIT and SLITtablets for individuals with allergies to other allergens have also been conducted as cost-minimization analyses. 25,26 The cost-minimization model was developed in Microsoft Excel

| Perspective, time horizon, and discounting
The analysis compared the costs of ITULAZAX® with ALUTARD SQ® from a Danish societal perspective over a 3-year time horizon, corresponding to the length of treatment to achieve disease modification recommended in international treatment guidelines. Future costs were not discounted in the base case analysis because the short time horizon and nature of the costs under consideration are comparable to those in a budget impact analysis in which discounting of future costs is not recommended. 28 Discount rates were explored in one-way sensitivity analyses.

| Dosing and resource use
ITULAZAX® and ALUTARD SQ® dosing was modeled in line with the respective summaries of product characteristics (SmPCs). One ITU-LAZAX® tablet was assumed to be taken daily, while for ALUTARD SQ®, the "conventional initial therapy" up-dosing scheme was used (Table S1), followed by a transition via one 100,000 SQ-U injection after 2 weeks, one 100,000 SQ-U after another 4 weeks, and then an ongoing 6-weekly maintenance dose of 100,000 SQ-U. Both treatments were assumed to be taken perennially in line with the SmPCs. As AIT has been shown to bring about a long-lasting disease-modifying effect, the European Academy of Allergy and Clinical Immunology Guidelines note that: "for patients with AR a minimum of 3 years of AIT is recommended to achieve long-term efficacy after treatment discontinuation". 29 Based on treatment guidelines, all individuals using ITULAZAX® or ALUTARD SQ® incurred the cost of 3 years of treatment. In the base case analysis, adherence to both treatments was assumed to be 100%.
The base case analysis evaluated a scenario spanning three different care settings in Denmark: general practice, specialist, and hospital-based care. The distribution between care settings during SCIT and SLIT treatment initiation and maintenance were based on 2018 data from the Danish Health and Medicines Authority (own calculations based on numbers from Sundhedsdatastyrelsen; Figure 1). The specialist tariffs were based on the current tariff values for an ear-nose-throat (ENT) specialist. The total number of visits was assumed to be the same across the three care settings for the given treatment modality (SCIT or SLIT); after a first dose visit, individuals treated with ITULAZAX® were assumed to require one annual evaluation consultation with a general practitioner (GP), specialist, or at the hospital depending on the care setting ( Figure 1).
Individuals treated with ALUTARD SQ® were assumed to require one GP appointment, specialist consultation, or hospital appointment for every injection. In year 1 (covering the up-dosing phase; Table S1), this would correspond to a total of 22 healthcare professional (HCP) interactions: 15 titration visits, 2 transition visits, and 5 maintenance visits. This would then be followed by an average of 8.7 HCP interactions per year for administration of the ALUTARD SQ® maintenance dose in all subsequent years.

| Costs
Costs of interacting with HCPs were based on a tariff-based microcosting approach (i.e. based on the sum product of a tariff-based unit cost and resource use estimate). Costs in each setting were calculated on a per-visit basis based on tariff data (Table 1). [30][31][32] In the specialist setting, the annual visit for SLIT, and one of the 8.7 visits for SCIT, were coded as the annual control visit which, in the case of RØNBORG ET AL. medicinpriser.dk; Table 2). 33 The cost of ALUTARD SQ® was based on the "Alk (108) Betula verrucosa" titration pack price during the up-dosing phase, followed by the 100,000 SQ-U/ml maintenance pack price for all injections after the up-dosing.

| Indirect costs
The ability to capture indirect costs was built into the model using a human capital approach based on absenteeism and presenteeism data from the TT-04 trial (Table 3). 35 Table 4) ( Table 5).

| RESULTS
The total cost of treatment over 3 years was estimated to be DKK   The present study has limitations that should be acknowledged when interpreting the findings. The first potential limitation is the evidence base on which clinical equivalence was assumed. As no T A B L E 4 Proportions of patients requiring symptom-relieving medication and average dosing during the tree pollen season (TPS) based on the TT-04 randomized controlled trial (RCT), and Danish acquisition costs as used in sensitivity analyses Indeed, it is not possible to definitively demonstrate that two treatments have an identical effect. 41 Based on a combination of clinical data on ITULAZAX® from TT-04 and meta-analyses comparing other SCIT and SLIT products, it is unlikely that any differences in efficacy, should they exist, would be clinically meaningful. 21,22 One area in which differences may exist between SCIT and SLIT is in the incidence and nature of local adverse reactions. Between 26% and 86% of patients experience local reactions to SCIT such as pruritus and/or erythema (>2.5 cm), while the most common reactions to SLIT involve the oromucosal or gastrointestinal regions. 42 However, reactions tend to be mild in nature and occur most frequently during the titration phase of treatment and would therefore be unlikely to drive meaningful differences in incremental economic outcomes. 40 Given the assumption of clinical equivalence, no further differences in cost outcomes would be anticipated between the treatments beyond those reported, but additional absolute direct and/or indirect nially. 43 Secondly, the costs of asthma were not captured in the present analysis. While between 15% and 38% of patients with AR have allergic asthma, given the assumption of equivalence between SCIT and SLIT, the exclusion of asthma treatment costs would not be anticipated to drive a further difference in costs between SCIT and SLIT. 15,44,45 In the base case analysis, adherence to both treatments was assumed to be 100% to facilitate an unbiased comparison, increase the interpretability of the findings, and comply with the foundational assumption of equivalent efficacy in cost-minimization analyses. Evidence from real-world studies suggests that patient adherence to SLIT and SCIT products is lower, with previous studies reporting adherence rates to SCIT and SLIT products to be highly variable; between 7% and 81% for SLIT and between 23% and 83% with SCIT. 37